5-amino-4-methoxyisoxazoles and 3-amino-4-methoxyisoxazoles

ABSTRACT

5-AMINO-4-METHOXY-3-ALKYLISOXAZOLES AND 3-AMINO-4METHOXY-5-ALKYLISOXAZOLES, INTERMEDIATES FOR THE PREPARATION OF ANTIBACTERIAL N1-(4-METHOXY-3-ALKYL-5-ISOXAZOLYL)SULFANILAMIDES AND N1-(4-METHOXY-5-ALKYL-3-ISOXAZOLYL)SULFANILAMIDES, RESPECTIVELY, ARE PREPARED AND DESCRIBED.

United States Patent O Int. Cl. C07d 85/22 U.S. Cl. 260-307 H 4 ClaimsABSTRACT OF THE DISCLOSURE 5-amino-4-methoxy-3-alkylisoxazoles and3-amino-4- methoxy-S-alkylisoxazoles, intermediates for the preparationof antibacterial N -(4-methoxy-3-all yl-5-isoxazolyl)sulfanilamides andN -(4-methoXy-5-alkyl-3-is0Xazolyl)sulfanilamides, respectively, areprepared and described.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisionof U.S. Pat. application Ser. No. 682,551, filed Nov. 13, 1967 now U.S.Pat. No. 3,547,973, issued Dec. 15, 1970, which in turn is a division ofU.S. Pat. application Ser. No. 446,068, filed Apr. 6, 1965 now U.S. Pat.No. 3,400,122, issued Sept. 3, 1968.

BRIEF SUMMARY OF THE INVENTION The invention relates to4-methoxy-S-alkylisoxazoles, 5-an1ino-4-methoXy-3 alkylisoxazoles, and3-amino-4- methoxy-S-alkylisoxazoles which are useful intermediates forthe corresponding antibacterial N -(4-methoxy-3-alkyl-S-isoxazolyl)sulfanilamides and N -(4-methoxy-5-alkyl-3-isoxazolyl) sulfanilamides.

In another aspect, the invention relates to intermediates of theformulas R- i CHCEN and CN RC 01=c wherein R is hydrogen or lower alkyl.

DETAILED DESCRIPTION This invention relates to sulfonamides and moreparticularly relates to sulfonamides of the formulas and to methods fortheir preparation. In the above formulas R is hydrogen or lower alkyl.

3,706,761 Patented Dec. 19, 1972 Compounds of Formulas I and II areprepared accordmg to the following reaction schemes:

Reaction Scheme I O I R-(E CHgOCHa O=CHN(CHa)i (III) (IV) R\ 9 C H R\/CHO /C=C\ /C=C\ Ci CHO Ci 0 CHa (Va) (Va) WQLOELH (I? RC=COOH: R-CCHCEN CH ([3 airali metal lower 0 H3 alkoxide or hydroxide N (VII) (VI)l NHzOH 1. YQ-SOzX (IX) CH OC:CNH2

| l 2. alkali metal hydroxide R-C O \N/ 3. conversion of Y to NH2, ifnecessary (VIII) CH3O('J=(l3NHSO NH= R-C O Reaction Scheme II R\ OC/HaR\ /CHO NH OH /OCH;

=o c=o RCCl=G Cl CHO Cl OCHa CH=NOH /1L1 OCH: 0 (X1) (XII) 1. YQ-SOQX(IX) 2. alkali metal hydroxide 3. conversion of Y to NH2, if necessaryR-C /N In the above Reaction Schemes I and II, R is hydrogen or loweralkyl, X is chlorine or bromine, preferably chlorine, and Y is aprotected amino group or an amino group precursor, i.e., a group whichcan be converted to an amino group through reduction or hydrolysis, forexample, nitro, nitroso, azo, hydrazo, hydrazido, carbalkoxyamino,carbobenzyloxyamino, etc., or preferably an acylamido group, forexample, an alkanoylamido group, preferably a lower alkanoylarnidogroup, e.g., acetamido, propionylamido, etc., or a benzamido orsubstituted benzamido group, e.g., alkylor halo-substituted benzamido.

In Reaction Scheme I a methoxy methyl ketone of Formula III is reactedwith dimethyl formamide (IV) in the presence of phosphorus oxychlorideor phosgene, preferably at a temperature in the range of from about 0 toabout 100 C. to form a mixture of aldehydes of Formulae Va and Vb. Thismixture of aldehydes is then reacted with a mineral acid addition saltof hydroxylamine, e.g., hydroxylamine hydrochloride, hydroxylaminesulfate, etc., preferably at a temperature in the range of from about 35to about 85 C., and preferably in an inert solvent, e.g., a loweralkanol solvent such as methanol, ethanol, etc., to form a4-methoxy-5-lower alkyl isoxazole of Formula VI. Compound VI is reactedwith an alkali metal lower alkoxide, e.g., sodium methoxide, sodiumethoxide, etc., or an alkali metal hydroxide, e.g., sodium hydroxide,potassium hydroxide, etc., preferably at a temperature in the range ofabout 20 to about 65 C. to form a ketonitrile of Formula VII. Theketonitrile of Formula VII is reacted with a. mineral acid addition saltof hydroxylamine, e.g., hydroxylamine hydrochloride, etc., preferably inthe presence of water, to form an aminoisoxazole of Formula VIII. Thisaminoisoxazole is then treated with a sulfonyl halide of Formula IX inthe presence of an acid binding agent such as an amine, e.g., pyridine,trimethylamine, etc., to form a sulfanilyl compound. The latter istreated with an aqueous alkali metal hydroxide, e.g., sodium hydroxide,potassium hydroxide, etc.; and finally the Y group is converted toamino, it necessary, by a known procedure in the sulfonamide art. WhereY is a group hydrolyzab'le to amino such as acetamido, hydrolysis of thehydrolyzable group takes place upon treatment with the alkali metalhydroxide to yield a compound of Formula I directly. However, where Y isan amino group precursor which is reducible to an amino group, then astandard reduction reaction such as hydrogenation with a palladiumcatalyst, is carried out to give a compound of Formula I.

Compounds of Formula II are prepared according to Reaction Scheme II bytreating a mixture of aldehydes of Formulae Va and Vb with hydroxylamineunder alkaline conditions, i.e., in the presence of a base, e.g., analkali metal carbonate such as sodium carbonate, an alkali metalhydroxide such as sodium hydroxide, potassium hydroxide, etc., an alkalimetal lower alkoxide such as sodium methoxide, sodium ethoxide, etc., toform an oxime of Formula X (which is probably a mixture of cis-transisomers). The oxime of Formula X is dehydrated by the use of phenylisocyanate, preferably in the presence of an inert hydrocarbon solvent,e.g., benzene, toluene, hexane, etc., at a temperature in the range ofabout 20 to about 85, to form a nitrile of Formula XI. The nitrile ofFormula XI is then reacted with hydroxylamine under alkaline conditions,e.g., in the presence of an alkali metal hydroxide such as sodiumhydroxide, potassium hydroxide, etc., an alkali metal lower alkoxidesuch as sodium methoxide, sodium ethoxide, etc., to form anaminoisoxazole of Formula XII. The aminoisoxazole of Formula XII is thenreacted with a sulfonyl halide of Formula IX in the presence of an acidbinding agent such as an amine, e.g., pyridine, trimethylamine, etc., toform a sulfanilyl derivative which is treated with an alkali metalhydroxide as above, and the Y group converted to NH if necessary (asdescribed above for Reaction Scheme I) to form a compound of Formula II.

Preferred compounds of Formulae I and II are those wherein R is methyl.

The term lower alkyl used herein is to be understood to refer to analkyl group having from 1 to 7 carbon atoms, which can be eitherstraight or branched chain, e.g., methyl, ethyl, propyl, isopropyl,butyl, heptyl, hexyl, etc.

Compounds of Formulae I and II and their base addition salts withpharmaceutically acceptable bases, such as sodium hydroxide,diethanolamine, etc., are antibacterial agents useful in the same manneras known sulfonamides, e.g., sulfadimethoxine. They are characterized bya wide spectrum of antibacterial activity. They can be employed in oralor parenteral dosage forms or for topical application such as in salves,otic formulations, etc., in combination with common pharmaceuticaladjuvants. Typical dosage forms are given below:

TABLET FORMULATION Per tablet, mg.

N -(-methoxy 3 methyl 5 isoxazolyl)-sulfanil- Procedure (1) N (4 methoxy3 methyl 5 isoxazolyl) sulfanilamide, corn starch, and lactose werethoroughly mixed in suitable blending equipment and granulated with a 10percent gelatin solution.

(2) The moist mass was passed through a No. 12 screen, and the granuleswere dried on paper lined trays overnight.

(3) The dried granules were passed through a No. 14 screen and placed ina suitable mixer. The talcum and magnesium stearate were added andblended.

(4) The granulation was compressed into tablets weighing approximately650 mg. each, using punches having an approximate diameter of 12.7 mm./2"). The final tablet thickness was about 5.35 mm.

fanilamide 412.0

Diethanolamine 159.0 Sodium metabisulfite 2.0

Water for injection USP, q.s. ad 1.0 cc.

Procedure (1) The sodium metabisulfite was dissolved in the water forinjection in a suitable size glass container (glass-lined container mayalso be used).

(2) Successive portions of the N (4 methoxy 3- methyl 5isoxazolyl)sulfanilamide were suspended in the solution and dissolved bythe addition of somewhat less than the equivalent quantity ofdiethanolamine until the required concentration solution was reached.

(3) The solution was filtered through a filter press to remove the grossparticles, and then through a No. 015 candle to achieve final clarityand sterility.

(4) The solution was filled under aceptic conditions into 5 cc. ambervials, sealed, and sterilized for 20 minutes at 250 F.

(5) The ampuls were inspected, and any ampuls showing insoluble materialwere rejected.

TABLET FORMULATION Per tablet, mg. N (4 methoxy 5 methyl 3isoxazolyl)sulfanilamide 505 Corn starch 29 Lactose 84 Gelatin l2 Talcum15 Magnesium stearate 5 Procedure (3) The dried granules were passedthrough a No. 14 screen and placed in a suitable mixer. The talcum andmagnesium stearate were added and blended.

(4) The granulation was compressed into tablets weighing approximately650 mg. each, using punches having an approximate diameter of 12.7 mm.(/z"). The final tablet thickness was about 5.35 mm.

PARENTERAL FORMULATION Mg./cc. N (4 methoxy 5 methyl 3isoxazolyl)sulfanilamide (claim 400 mg.) 412.0 Diethanolamine 159.0Sodium metabisulfite 2.0 Water for injection USP, q.s. ad 1.0 cc.

Procedure (1) The sodium metabisulfite was dissolved in the water forinjection in a suitable size glass container (glasslined container mayalso be used).

(2) Successive portions of the N (4 methoxy 5- methyl 3isoxazolyl)sulfanilamide were suspended in the solution and dissolved bythe addition of somewhat less than the equivalent quantity ofdiethanolamine until the required concentration solution was reached.

(3) The solution was filtered through a filter press to remove the grossparticles, and then through a No. 015 candle to achieve final clarityand sterility.

(4) The solution was filled under aseptic conditions into 5 cc. ambervials, sealed, and sterilized for 20 minutes at 250 F.

(5) The ampuls were inspected, and any ampuls showing insoluble materialwere rejected.

The following examples are given for illustration purposes only and arenot meant to limit the invention.

EXAMPLE 1 Preparation of N -(4-methoxy-3-methyl-5-isoxazolyl)sulfanilamide N,Ndimethylformamide (438 g.) was cooled in an icesaltbath while phosphorus oxychloride (452 ml.) was added at 2-5 withvigorous stirring over a period of two hours. The cold bath was removedand the reaction stirred for 30 minutes, during which time thetemperature rose to 15. The mixture was then warmed momentarily on awater bath and the temperature maintained at 20-24 for 30 minutes.

With cooling below methoxyacetone (176 g.) was added over a period of 25minutes and the bath was removed to permit a spontaneous heatgeneration. Within minutes the temperature reached 35 and was controlledat 35-40" for 35 minutes by intermittent cooling. The mixture was pouredinto 2 kg. of cracked ice. Sodium chloride (400 g.) was added and themixture allowed to warm to 15. While maintaining the temperature between15 and 22 by intermittent cooling with an ice bath, the mixture wasextracted with three 1200 ml. portions of ether. The ether extracts werecombined and washed successively with saturated sodium chloride (400ml.), saturated sodium bicarbonate solution (400 ml.), and finally withsaturated sodium chloride solution (250 ml.) After drying with sodiumsulfate, the ether solution was concentrated on the steam bath and theresidue distilled; yield of a cis-trans mixture of 3 chloro 2 methoxy-2-butenal, 142 g.; boiling point 7080/20 mm.

3-chloro-2-methoxy-2-butenal (cis-trans mixture) (100 g.), hydroxylaminehydrochloride (77.5 g.), and methanol (750 ml.) were refluxed for twohours. When the mixture had cooled to 40 a solution of cadmium chloride(450 g. of CdCl '2 /2 H in water (400 ml.) was added. The cadmiumchloride complex was allowed to crystallize overnight before filteringand washing with methanol and ether.

The complex (21.8 g.) was mixed with ml. of water and distilled,collecting about 50 ml. of distillate consisting of two phases. Thedistillate was saturated with sodium chloride and extracted with five 10ml. portions of ether. The ether was dried with sodium sulfate anddistilled on the steam bath. The residue, 4-methoxy-5-methylisoxazole(6.1 g.), was distilled under reduced pressure; yield 4.81 g.; boilingpoint 108/100 mm.

4-methoxy-S-methylisoxazole (4.81 g.) was added to a solution of sodiummethoxide (4.60 g.) in methanol (50 ml.) with momentary cooling to keepthe reaction temperature below 40". At this point the sodium salt of theketonitrile partially precipitated, but was allowed to remain in themixture. After standing for one hour, the methanol was evaporated invacuo. Water (10 ml.) and hydroxylamine hydrochloride (2.98 g.) wereadded, and the mixture'was warmed to 60 for 30 minutes. After standingfor about 16 hours at room temperature, the mixture was extracted withfive 10 ml. portions of ether. The ether extracts were dried with NaSOand evaporated in vacuo to leave a 4.90 g. residue. Crystallization fromether (10 ml.) and petroleum ether (2 ml.) in an ice-salt bath gave themajor portion of product, 5-amino-4-methoxy-3- methylisoxazole, 3.30 g.,melting point 48-49.

The filtrate was evaporated, and the residue crystallized from ether .(2ml.) and petroleum ether (1 ml.) to obtain a second crop: 0.95 g.,melting point 48-49". Total yield, 4.25 g.

5 amino-4-methoxy-3-methylisoxazole (3.75 g.) was dissolved in drypyridine (38 ml.) and p-acetylaminobenzenesulfonyl chloride (15.1 g.)was added. On stirring into solution the reaction temperature rose to 40where it was maintained by warming for 1% hours.

The mixture was cooled to room temperature, and diluted with water (375ml.). The oily precipitate was left standing overnight to solidify. Thecrude product, a bis (p acetylaminobenzenesulfonyl) compound (14.35 g.,darkens at 190, melts 224-225") was used directly.

A sample purified for analysis by crystalization from acetic acid meltedat 233234.

The bis(p acetylaminobenzenesulfonyl) compound (14.35 g.) and 144 ml. of10 percent w./w. aqueous sodium hydroxide were stirred and heated on thesteam bath for 40 minutes. Cooling and treatment with 25 percent aqueousacetic acid ml.) precipitated the product (7.20 g., melting point166-169). Crystallization from methanol (50 ml.) and water (100 ml.)gave the pure product, N (4-methoxy-3-methyl-5-isoxazolyl)sulfanilamide;yield 6.88 g.; melting point 168170.

EXAMPLE 2 Preparation of N (4-methoxy-5-methyl-3-isoxazolyl)sulfanilamide 3 chloro 2 methoxy-Z-butenal (cis-trans mixture) (122.0g.) was added with stirring to a solution of hydroxylamine hydrochloride(70 g.) and sodium hydroxide (40 g.) in 1 liter of water. The reactionwas stirred two hours, and the crude product filtered (101.4 g., meltingpoint 6885). This material consisted of a mixture of isomers of3-chloro-2-methoxy-2-butenal oxime.

Crystallization from ether (100 ml.) and petroleum ether .(400 ml.)yielded the isomer formed as the major product; yield 59.3 g.; meltingpoint 9194.

Further recrystallization for analysis gave a melting point of 95-86.

Evaporation of the filtrate and tritnration of the residue withpetroleum ether gave a mixture enriched in the second isomer (29.5 g.,melting point 52-67"). Further crystallization of a similarly obtainedmaterial gave a product, which still contained approximately one-thirdof the higher melting isomer.

3-ch1oro-2-methoxy-2-butenal oxime (melting point 91- 94) (59.3 g.) wasadded to a solution of phenyl isocyanate (94.5 g.) and triethylamine(3.5 ml.) in benzene (600 ml.). After stirring for 15 minutes, themixture was cautiously heated on the steam bath and refluxed 2 /2 hours.

The mixture was cooled, and the precipitate of sym.- diphenylurea wasfiltered. The benzene solution was concentrated on the steam bath, andthe residue, 3-chloro-2- methoxy-Z-butenenitrile, distilled in vacuo;yield 32.5 g.; boiling point 5962/20 mm.

A mixture of 3-chloro-2-methoxy-2-butenenitrile ,(21.0 g.),hydroxylamine hydrochlorile (16.8 g.), sodium methoxide (21.6 g.), andmethanol (200 ml.) was stirred at 40 for 18 hours. The mixture wasfiltered and the filtrate evaporated to dryness in vacuo. The residuewas extracted with warm ether (200 ml.). The ether solution wasevaporated in vacuo and the residue, 3-amino-4-methoxy-S-methylisoxazole (15.6 g.) crystallized from ether (20 ml.) at10 to give the major portion of the product 1.05 g., melting point90-92).

A further amount of aminoisoxazole was recovered from the filtrate. Theresidue after evaporation of the ether was vigorously shaken with water(140 ml.), centrifuged, and the aqueous solution decanted. Evaporationof the water left a residue. (4 g.) which crystallized from ether (6ml.) at --l to give additional product (0.43 g., melting point 8589).Total yield, 1.48 g.

A sample purified by recrystallization from ether melted at 9193.

3-amino-4-methoxy-5-methylisoxazole (1.35 g.) was dissolved in drypyridine (13.5 ml.), and p-acetylaminobenzenesulfonyl chloride (5.42 g.)was added. On stirring into solution, the temperature rose to 40, whereit was maintained by warming for 1% hours. The mixture was cooled, anddiluted with Water (140 ml.). The precipitate, abis(p-acetylaminobenzenesulfonyl) compound, solidified on standingovernight (4.82 g., melting point 230-235 Recrystallization of a samplefirom acetic acid raised the melting point to 239-241 The his product(4.82 g.) and ml. of 10 percent w./w. aqueous sodium hydroxide werestirred on the steam bath for one hour. Cooling and treatment with 25percent acetic acid (35 ml.) precipitated the product N -(4- methoxy 5methyl-3-isoxazolyl)sulfanilamide (2.00 g., melting point 189-191),which was recrystallized from methanol (40 ml.) and water ml.); yield1.83 g.; melting point 197-199=.

We claim:

1. A compound of the formula C'H 0 G=CNH wherein R is selected from thegroup consisting of hydrogen and lower alkyl.

2. A compound according to claim 1, wherein R is methyl, i.e.,5-amino-4-tnethoxy-3-methylisoxazole.

3. A compound of the formula CH30CCNH2 wherein R is selected from thegroup consisting of hydrogen and lower alkyl.

4. A compound according to claim 3, wherein R is methyl, i.e.,3-amino-4-methoxy-S-methylisoxazole.

References Cited UNITED STATES PATENTS 2,430,094 11/ 1947 Wuest et a1.260-239.6 3,133,078 5/1964 Steiger 260-307 3,192,216 6/1965 Gray et a1260-2564 NICHOLAS S. RIZZO, Primary Examiner R. V. RUSH, AssistantExaminer

